MDR1 Genetic Polymorphism Does Not Modify either Cell Permissiveness to HIV-1 or Disease Progression before Treatment

Nonphysiological overexpression of the ABC transporter Pglycoprotein (P-gp), which is encoded by MDR1, has been associated with reduced susceptibility to human immunodeficiency virus (HIV) type 1 infection in vitro. We analyzed (1) the expression and genotype of MDR1 and their relationship to HIV-1 permissiveness of CD4+ T cells from 128 healthy blood donors and (2) the role that alleles of MDR1 exons 21 and 26 play in modifying disease progression in 411 HIV-1-infected individuals. Differences in physiological levels of MDR1 expression did not modify HIV-1 infection in vitro, nor did MDR1 alleles and haplotypes significantly influence either permissiveness to infection in vitro or disease progression in vivo before the initiation of treatmen

Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients

Objective: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. Methods: A low oral dose of midazolam (MID) (0.075mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). Results: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P<0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P<0.0001), 17-fold lower with efavirenz+ritonavir (three patients; 0.21, 0.05-0.47; P=0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P=0.0007), and 7-fold lower with nevirapine+(ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P=0.03). CYP3A activity was lower in the efavirenz+ritonavir group (P=0.01) and in the ritonavir group (P=0.04) than in the nelfinavir group, although already strongly inhibited in the latter. Conclusion: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200mg/day b.i.d.) or of nelfinavir at standard dosages (2,500mg/day b.i.d.

Drug-Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV : Are They Different from Non-Pregnant Individuals?

Although the separate effects of drug-drug interactions and pregnancy on antiretroviral drug pharmacokinetics have been widely studied and described, their combined effect is largely unknown. Physiological changes during pregnancy may change the extent or clinical relevance of a drug-drug interaction in a pregnant woman. This review aims to provide a detailed overview of the mechanisms, magnitude, and clinical significance of antiretroviral drug-drug interactions in pregnant women. We performed a literature search and selected studies that compared the magnitude of drug-drug interactions with antiretroviral drugs in pregnant vs non-pregnant women. Forty-eight papers examining drug-drug interactions during pregnancy were selected, of which the majority focused on pharmacokinetic boosting. Other selected studies examined the drug-drug interactions between efavirenz and lumefantrine, efavirenz and tuberculosis drugs, etravirine and tenofovir disoproxil fumarate, atazanavir and tenofovir disoproxil, and mefloquine and nevirapine in pregnant compared to non-pregnant women. The clinical significance of antiretroviral drug-drug interactions changed during pregnancy from a minimal effect to a contra-indication. In almost all cases, the clinical significance of a drug-drug interaction was more relevant in pregnant women, owing to the combined effects of pregnancy-induced physiological changes and drug-drug interactions leading to a lower absolute drug exposure. Multiple studies show that the clinical relevance of a drug-drug interaction can change during pregnancy. Unfortunately, many potential interactions have not been studied in pregnancy, which may place pregnant women living with human immunodeficiency virus and their newborns at risk

COVID-19 treatment in patients with comorbidities: Awareness of drug-drug interactions

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Development of a physiologically-based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs.

There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations

Effect of Obesity on the Exposure of Long-acting Cabotegravir and Rilpivirine: A Modeling Study.

BackgroundObesity is increasingly prevalent among people with human immunodeficiency virus (HIV, PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in silico trials using physiologically based pharmacokinetic (PBPK) modeling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections.MethodsOur PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/ overweight (body mass index [BMI] 30 kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60 kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (area under the curve [AUC]) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25 kg/m2).ResultsObesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35 kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40 kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration, but this was less frequent with the monthly administration.ConclusionsMorbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment

Revisiting systemic treatment of bacterial endophthalmitis: a review of intravitreal penetration of systemic antibiotics

Adjunctive systemic antibiotic therapy for treatment of bacterial endophthalmitis is controversial but common practice due to the severity of the disease. In absence of guidance documents, several antibiotic regimens are being used without applying evidence-based prescribing, thus leading to inappropriate treatment of this serious eye condition.; To summarize available data on intravitreal penetration of systemically administered antibiotics and to discuss their usefulness from a microbiological and pharmacological point of view.; We performed a systematic PubMed search of studies investigating antibiotic concentrations in the vitreous after systemic administration in humans, and selected animal models.; The best-documented agents achieving therapeutic levels in the vitreous are meropenem, linezolid and moxifloxacin. Vancomycin, cefazoline, ceftriaxone, ceftazidime, imipenem and trimethoprim-sulfamethoxazole reach levels justifying their use in specific situations. Available data do not support the use of ciprofloxacin, levofloxacin, aminoglycosides, aminopenicillins, piperacillin, cefepime, and clarithromycin. With very limited but available promising data, the use of daptomycin and rifampicin deserves further investigation.; The choice of the adjunctive systemic antibiotic agent - in situations where considered relevant for treatment - must to date be made on an individual base, considering microbiological aspects as well as operative status and inflammation of the eye. This review gives a systematic overview of antibiotic options and provides guidance to the clinician striving for optimal systemic antibiotic treatment of bacterial endophthalmitis

Collaborative challenges of multi-cohort project in pharmacogenetics - why time is essential for meaningful collaborations.

UNSTRUCTURED Multi-cohort projects in medicine provide an opportunity to investigate scientific questions beyond the boundaries of a single institution, and to increase sample size for more reliable results. However, the complications of these kinds of collaborations arise during management, with many administrative hurdles. Hands-on approaches and lessons learned from previous collaborations provide solutions for optimized collaboration models. Here, we use our experience in running the Swiss multi-cohort project PGX-link to show the strategy we used to tackle different challenges from project set up to getting the relevant permits, including ethics approval. We set PGX-link into an international context, since our struggles were similar to those encountered during the SYNCHROS project. We provide ad-hoc solutions for cohorts, general project management strategies, and suggestions for unified protocols between cohorts that would ease current management hurdles. Project managers are not necessarily familiar with medical projects, and even if they are, they are not aware of the intricacies behind decision making, and consequently of the time needed to set up multi-cohort collaborations. This paper is meant to be a brief overview of what we went through with our multi-cohort project and provides the necessary practices for future managers

Collaborative Challenges of Multi-Cohort Projects in Pharmacogenetics-Why Time Is Essential for Meaningful Collaborations

Multi-cohort projects in medicine provide an opportunity to investigate scientific questions beyond the boundaries of a single institution and endeavor to increase the sample size for obtaining more reliable results. However, the complications of these kinds of collaborations arise during management, with many administrative hurdles. Hands-on approaches and lessons learned from previous collaborations provide solutions for optimized collaboration models. Here, we use our experience in running PGX-link, a Swiss multi-cohort project, to show the strategy we used to tackle different challenges from project setup to obtaining the relevant permits, including ethics approval. We set PGX-link in an international context because our struggles were similar to those encountered during the SYNCHROS (SYNergies for Cohorts in Health: integrating the ROle of all Stakeholders) project. We provide ad hoc solutions for cohorts, general project management strategies, and suggestions for unified protocols between cohorts that would ease current management hurdles. Project managers are not necessarily familiar with medical projects, and even if they are, they are not aware of the intricacies behind decision-making and consequently, of the time needed to set up multi-cohort collaborations. This paper is meant to be a brief overview of what we experienced with our multi-cohort project and provides the necessary practices for future managers

Effect of SLCO1B1 c.521T>C polymorphism on the lipid response to statins in people living with HIV on a boosted protease inhibitor-containing regimen

AIMS: We previously observed that some individuals on HIV boosted protease inhibitor-containing regimen do not achieve their lipid targets despite elevated statin concentrations. This study evaluated whether the common single polymorphism c.521T>C in SLCO1B1, associated with reduced statin uptake in the liver, could explain this observation. METHODS: People living with HIV in the Swiss HIV Cohort Study were eligible if they were on a boosted protease inhibitor concomitantly with a statin for at least 6 months and if their SLCO1B1 genotype was available. Furthermore, their lipids had to be documented before and after the introduction of the statin. The statin efficacy was defined as % change in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides levels after statin initiation compared to pretreatment levels. Lipid response was adjusted for differences in potency and dose between statins. RESULTS: In total, 88 people living with HIV were included, of whom 58, 28 and 2 carried the SLCO1B1 TT, TC and CC genotypes, respectively. The change in lipid levels after statin initiation tended to be lower in carriers of the polymorphism although the difference was not statistically significant (TT vs. TC/CC: total cholesterol: -11.7 vs. -4.8%; low-density lipoprotein- cholesterol: -20.6 vs. -7.4%; high-density lipoprotein-cholesterol: 1.6 vs. 0%; triglycerides: -11.5 vs. -7.9%). In the multiple linear regression, change in total cholesterol was inversely correlated with the total cholesterol level prestatin treatment (coefficient -6.60, 95% confidence interval: -9.63 to -3.56, P < .001). CONCLUSION: The lipid-lowering effect of statins tended to be attenuated by SLCO1B1 polymorphism and progressively declined as total cholesterol under the boosted protease inhibitor treatment decreased